Protein kinases represent a large family of enzymes, which catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. Common points of attachment for the phosphate group to the protein substrate include, for example, a tyrosine, serine or threonine residue. Examples of kinases in the protein kinase family include, without limitation, Abl1 (v-Abl Abelson murine leukemia viral oncogene homolog 1), Akt, Alk, Bcr-Abl1, Blk, Brk, Btk, c-Kit, c-Met, c-Src, c-Fms, CDK1-10, b-Raf, c-Raf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Flt-1, Fps, Frk, Jak, KDR, MEK, PDGFR, PIK, PKC, PYK2, Ros, Tie, Tie2, and Zap70. Due to their activity in numerous cellular processes, protein kinases have emerged as important therapeutic targets.
PI3 kinases (phosphoinositide 3-kinases, PI3Ks) are family of lipid kinases capable of phosphorylating the 3′-OH of the inositol ring of phosphoinositides. The phosphoinositol-3-kinase family is divided into three different classes: Class I, Class II, and Class III. The classifications are based on primary structure, regulation, and in vitro lipid substrate specificity. PI3 kinases are responsible for coordinating a diverse range of cell functions including proliferation, cell survival, degranulation, vesicular trafficking and cell migration, which in turn are involved in cancer.
To this end, attempts have been made to identify small molecules which act as PI3 kinases inhibitors. For example, pyrimidine derived compounds (international patent applications WO2007084786 and WO2008098058) have been described as PI3 kinases inhibitors.
Thus, the compounds that can inhibit protein kinases such as PI3 and other kinases activity either independently or together can be used to treat human diseases such as cancers.